As a developing Physician-Scientist, my career goal is to cultivate and integrate my experiences as a clinician and investigator so that I may translate new mechanistic insights into the pathophysiolgical basis of diabetes to the bedside. I am committed to a career in academic medicine with the goal of developing clinical and scientific expertise in diabetes with a focus on genes involved in pancreatic development and insulin secretion. The studies outlined in this proposal will allow me to apply and extend my training as a clinical investigator and will be complemented by course work in clinical investigation and genetics. The University of Maryland and Johns Hopkins Bayview Medical Center GCRC provide a rich environment for collaboration and support, both at an institutional level and within Dr. Alan Shuldiner's laboratory. The mentored-based work and specific career development plan that Dr. Shuldiner and I have developed will provide me with the skills needed to excel as an independent research career. Type 2 diabetes mellitus is a polygenic, heterogeneous disorder characterized by the presence of beta cell dysfunction and insulin resistance. We hypothesize that common mutations in genes involved in insulin secretion and/or pancreatic development result in abnormal insulin secretion which in turn contribute to the development of type 2 diabetes. Furthermore, we hypothesize that having polymorphisms in more than one gene may have additive effects on insulin secretion and increase the likelihood of developing type 2 diabetes. Polymorphisms have been identified in several genes known to effect insulin secretion and/or pancreatic development [e.g., pancreatic duodenal homeobox factor-1 (PDX-1) Asp76Asn, Beta 2/NeuroD Ala45Thr, insulin receptor substrate-2 (IRS-2) Gly1057Asp, and beta-3adrenergic receptor (beta3AR) Trp64Arg]. To test our hypotheses, we propose to prospectively recruit nondiabetic subjects with these polymorphisms and characterize insulin secretion using proinsulin levels, the insulin- modified frequently sampled intravenous glucose tolerance test and insulin oscillation studies. In specific aim I, subjects will have one of the polymorphisms and a normal genotype for the other three genes, and in specific aim 2, subjects will have two of the polymorphisms, and a normal genotype for the other two genes. Through these studies and unique recruitment scheme, we will determine the role of these polymorphisms in a polygenic model of diabetes that will lead to a new mechanistic understanding of the genetics and pathophysiology of type 2 diabetes and new preventive and therapeutic strategies.